tbuckley/cabot-search huggingface dataset:
Abstract 2221: Molecular analysis finds excision margin width predictive of recurrence in acral melanoma
Authors: Grace Heloise Attrill, Teresa A. Bailey, Trina Lum, Jordan W. Conway, Georgina V. Long, James S. Wilmott, Richard A. Scolyer
Journal: Cancer Research (2022)

Abstract Surgical excision with histologically clear margins results in cure of most melanoma patients. Involvement of the margins is associated with tumour recurrence and adverse outcomes. Determining whether or not the histological margins are involved by melanoma, particularly in situ melanoma, can be very difficult particularly in acral locations where insitu melanoma can be extremely subtle. This study sought to determine the proximity of acral melanoma in situ to the surgical excision margin using multiple methods including routine histopathological assessment, FISH (CCND1 amplification), and multiplex immunofluorescence (mIF: SOX10, p16, Cyclin D1 and PRAME) in primary acral melanomas with initially histopathologically reported clear excision margins of &amp;gt;0.3mm (n=85). The clear excision margins determined by each modality were compared between those melanomas which recurred (n=47) and those which remained recurrence-free at last follow-up (median = 46 months, range = 1-260 months) (n=35). Histopathologically confirmed excision margin width was smaller in the tumours of patients who recurred (mean = 7.083mm vs 9.964mm, p = 0.0811). Intratumoural CCND1 amplification was increased in recurrence-free patients in comparison to recurrence patients (16.2% vs 7.7%). FISH and mIF confirmed the correlation of intratumoural CCND1 amplification with Cyclin D1 expression SOX10+ melanoma cells (p=0.0347). No correlations between recurrence status and Cyclin D1, PRAME or p16 expression levels in the tumour or epidermis were identified. In histopathologically normal epidermal tissue as assessed on H&amp;E sections,Cyclin D1+, p16- and PRAME+ cells were classified as malignant cells when co-expressed with SOX10. Upon measuring the distance from the tumour margin to the nearest malignant cell, we found that malignant cells were closer to the tumour in recurrence patients in comparison to recurrence-free patients (mean = 7.324mm vs 9.464mm, p = 0.2735). These distances closely correlated with the excision margin width as determined via histopathological assessment (R2 = 0.7424, p&amp;lt;0.0001). In conclusion, histological assessment, FISH and mIF determined excision margins are highly correlative in acral melanomas. Narrower excision margins were associated with local recurrence of melanoma. Citation Format: Grace Heloise Attrill, Teresa A. Bailey, Trina Lum, Jordan W. Conway, Georgina V. Long, James S. Wilmott, Richard A. Scolyer. Molecular analysis finds excision margin width predictive of recurrence in acral melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2221.
FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer
Authors: Elizabeth S. Duke, Amy K. Barone, Somak Chatterjee, Pallavi S. Mishra-Kalyani, Yuan-Li Shen, Emasenyie Isikwei, Hong Zhao, Youwei Bi, Jiang Liu, Nam Atiqur Rahman, Emily Wearne, John K. Leighton, Maritsa Stephenson, Idara Ojofeitimi, Barbara Scepura, Abhilasha Nair, Richard Pazdur, Julia A. Beaver, Harpreet Singh
Journal: Clinical Cancer Research (2022)

Abstract On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4–13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9–3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15–0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling.
Abstract LB051: IL-6 and CCL18 mediate reciprocal interactions between VHL-deficient kidney cells and macrophages during development of ccRCC
Authors: Tien Hsu, Thi Ngoc Nguyen, Hieu-Huy Nguyen-Tran, Chen-Yun Chen
Journal: Cancer Research (2022)

Abstract Loss of the von Hippel-Lindau (VHL) tumor suppressor gene function accounts for 70-80% of all clear-cell renal cell carcinoma (ccRCC) cases, the most prevalent form of RCC. Accumulating evidence has indicated that ccRCC arises at the site of chronic inflammation; however, how the ccRCC tumor cells interact with the immune components of the microenvironment has remained unclear. In this study we employed unbiased proteomic and genomic analyses on components of the tumor microenvironment under different conditions. We have identified the molecular and cellular mechanisms that underlie the crosstalk between VHL-deficient kidney tubule cells and macrophages with relevance to tumor-associated inflammation and ccRCC development. We demonstrate that the VHL-deficient non-cancerous kidney epithelial cells, representing the early stage of ccRCC initiation, secrete IL-6 that recruits macrophages and induces their polarization toward the pro-tumorigenic M2 phenotype in vitro and in the mouse Vhlh gene conditional knockout model. The activated human macrophages reciprocally secrete CCL18 and TGF-beta1 to stimulate epithelial-to-mesenchymal transition (EMT) of the kidney tubule cells. Importantly, treatment with anti-IL-6 neutralizing antibody can rescue inflammatory, proliferative, and EMT phenotypes of Vhlh conditional knockout in vivo. Furthermore, in a human ccRCC xenograft model, exogenous human macrophages can significantly promote primary tumor growth and metastasis; and this oncogenic function is dependent on the expression of CCL18. These findings identify specific factors involved in a reciprocal crosstalk between the tumor cells and the immune components such as macrophages in the microenvironment. These results thus suggest an avenue for early intervention of ccRCC. Citation Format: Tien Hsu, Thi Ngoc Nguyen, Hieu-Huy Nguyen-Tran, Chen-Yun Chen. IL-6 and CCL18 mediate reciprocal interactions between VHL-deficient kidney cells and macrophages during development of ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB051.
Abstract 298: Targeting KRAS mutant non-small cell lung cancer with EGFR aptamer displaying 3WJ pRNA nanoparticles
Authors: Linlin Yang, Zhefeng Li, Peixuan Guo, Terence M. Williams
Journal: Cancer Research (2022)

Abstract Background and Purpose: KRAS mutations are one of the most common oncogenic mutations in human cancers, including non-small cell lung cancer (NSCLC), and have established roles in cancer pathogenesis and therapeutic resistance. Development of effective inhibitors of mutant KRAS represent a significant challenge. The field of three-way junction (3WJ) based RNA nanoparticles has advanced rapidly and shows promise as an effective in vivo siRNA delivery system. This aim of this study is to explore the potential of 3WJ-pRNA nanoparticles for specific and efficient delivery of KRASG12C siRNA to NSCLC cells harboring a KRASG12C mutation to effectively silence KRAS oncogenic activity. Experimental design: Multifunctional EGFRapt-3WJ-siKRASG12C nanoparticles were prepared using bottom-up self-assembly approach, and characterized by agarose gel shift assay, dynamic light scattering (DLS), and temperature gradient gel electrophoresis system (TGGE). Three NSCLC cell lines, H2122 and H2030 carrying KRASG12C, and H1299 with wild type KRAS were used in this study. Binding specificity and delivery efficiency of EGFRapt-3WJ-siKRASG12C nanoparticles in NSCLC cells were evaluated in vitro and in vivo. Biological effects of KRAS mutant silencing were assessed by in vitro functional assays, and in vivo tumor xenograft experiments. Results: Characterization of EGFRapt-3WJ-siKRASG12C by DLS showed 7.2 ± 0.5 nm average size, and TGGE indicated a melting temperature (Tm) of 51.77°C. Flow cytometry, IVIS lumina imaging assay, real-time quantitative PCR, western blot, and KRAS activity assay confirmed that EGFRapt-3WJ-siKRASG12C potently and selectively depleted cellular KRAS expression, resulting in suppression of downstream MAPK pathway signaling in KRASG12C NSCLC cells and in heterotopic tumor models. In addition, in vitro cell proliferation, migration/invasion, and chemotherapy and radiotherapy sensitivity assays, demonstrated that KRAS silencing by EGFRapt-3WJ-siKRASG12C suppressed NSCLC cell growth, migration/invasion ability, and sensitized NSCLC cells to chemotherapy or radiotherapy. In vivo, these nanoparticles led to regression of tumor growth in heterotopic models. Conclusions: Together, this study suggests that 3WJ pRNA based platform has clinical potential to suppress mutant KRAS activity for the treatment of KRAS driven human cancers, and warrants further development. Citation Format: Linlin Yang, Zhefeng Li, Peixuan Guo, Terence M. Williams. Targeting KRAS mutant non-small cell lung cancer with EGFR aptamer displaying 3WJ pRNA nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 298.
Abstract 5851: Negative regulation of p53 by ZnT1
Authors: Ben Brik, Kathleen Carino, Wade Narrow, Chris R. Harris, Xin Yu, Darren R. Carpizo
Journal: Cancer Research (2022)

Abstract Rationale and Background: p53 is a powerful tumor suppressor protein that also autorepresses by inducing expression of its own negative regulators, such as MDM2. Here we explore another potential mechanism for p53 autorepression, regulation of zinc metabolism. Proper folding of p53 requires zinc binding and cancer-associated mutations in p53 often lower the affinity of the mutant proteins for zinc. Our previous work showed that ZMC1, a zinc metallochaperone, can reactivate certain p53 mutants by raising intracellular zinc concentrations. Here we show that p53 activates transcription of ZnT1. ZnT1 can then export zinc from the cell, which in turn lowers p53 activity. Methods: To explore the relationship between ZnT1 and p53, we studied several human cancer cell lines under various conditions, including ZnT1 overexpression, ZnT1 silencing, and p53 activation. For silencing gene expression, we used CRISPR-Cas9 with a lentiviral vector to knock out ZnT1 and also employed shRNAs to knockdown expression of p53 or ZnT1. To analyze the relationship between TP53 and ZnT1 genes in clinical samples, data from cBioPortal were examined. Results: ZnT1 transcription increased after p53 was activated in several p53+ cell lines but did not increase in isogenic p53-null cell lines, suggesting that ZnT1 transcription is dependent on p53. p53 also bound to the ZnT1 promoter by chromatin immunoprecipitation assay, and activated transcription of a ZnT1/luciferase promoter fusion. Overexpression of ZnT1 decreased p21 transcription, indicating lowered p53 function; conversely, knockdown of ZnT1 increased p21 transcription. By cBioPortal analysis, ZnT1 gene amplifications were mutually exclusive with TP53 gene mutations in breast and lung tumors. Conclusion: These data suggest that autorepression of p53 occurs in part due to lowered intracellular zinc caused by upregulation of ZnT1. Citation Format: Ben Brik, Kathleen Carino, Wade Narrow, Chris R. Harris, Xin Yu, Darren R. Carpizo. Negative regulation of p53 by ZnT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5851.
Abstract 2956: Superenhancer-drvien SMC4 promote cell growth and proliferation in multiple myeloma
Authors: Yunlu Jia, Jianbiao Zhou, Tze-King Tan, Tae-Hoon Chung, Yongxia Chen, Enfan Zhang, Zhen Cai, Takaomi Sanda, Wee-Joo Chng
Journal: Cancer Research (2022)

Abstract Background Multiple myeloma (MM) is an incurable malignancy characterized by complex heterogeneous cytogenetic abnormalities. Defined as large clusters of cis-acting enhancers, super-enhancers (SEs) could promote oncogenic transcription to which cancer cells highly addicted. Structural maintenance of chromosome 4 (SMC4) is a core subunit of condensin complexes, which contributes to chromosome condensation and segregation. Here, we identified SMC4 as a novel SE-associated oncogene of myeloma cells, whose functional roles in MM remain largely elusive. Methods We performed H3K27ac ChIP-seq and RNA-seq on primary MM patient samples, MM cell lines, normal CD138+ plasma cell and lymphoma cell lines as the controls, then the ROSE analysis was used to annotate SEs and their associated genes. THZ1 as a transcriptional CDK7 inhibitor was used to further filter THZ1-responsive genes. Combined analysis of THZ1-sensitive and SE-associated gene uncovered a number of promising MM oncogenes as SMC4. The public data mining, RNA interference, CRISPR/Cas9 gene editing system, overexpression and a variety of cellular functional assays were performed to determine the oncogenic effects of SMC4 on MM malignant. Transcriptome analysis with SMC4 silencing and overexpression, and the underlying molecular mechanism of SMC4 oncogenic role in MM are ongoing. Results We have demonstrated SMC4 as one of the SE-associated genes specific to MM patient samples and cell lines. SMC4 was related to myelomagenesis with increased expression from MGUS, SMM to MM cases, and overexpression of SMC4 predicted poor overall survival of MM patients, suggesting its clinical relevance. SMC4 silencing in MM cells suppressed cell proliferation and lead to cell apoptosis. Repression of the SMC4-SE region also led to impairment of cell viability and cell growth, consistent with an oncogenic function. Conclusion In summary, our integrative approached by combing H3H27ac ChIP-seq, RNA-seq and THZ1-sensitive transcripts identified the landscape of SEs and novel oncogenic transcripts as SMC4 in MM. Mapping these acquired SEs and their associated genes may provide novel insight into understanding MM biology, and SMC4 may serve as novel therapeutic targets in MM. Citation Format: Yunlu Jia, Jianbiao Zhou, Tze-King Tan, Tae-Hoon Chung, Yongxia Chen, Enfan Zhang, Zhen Cai, Takaomi Sanda, Wee-Joo Chng. Superenhancer-drvien SMC4 promote cell growth and proliferation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2956.
Abstract 5796: Targeting poorly differentiated and anaplastic thyroid cancer microenvironment via TNF-α/TGF-β/LOX signaling to improve drug delivery and treatment efficacy
Authors: DIPRANJAN LAHA
Journal: Cancer Research (2022)

Abstract A major limitation of current systemic solid cancer therapies is the failure to effectively deliver drugs to cancer cells. Solid tumors have high cell density and poor lymphatic drainage, leading to higher interstitial fluid pressure (IFP). We previously showed that the tumor microenvironment of poorly-differentiated (PDTC) and anaplastic thyroid cancer (ATC) can be selectively and effectively treated with nanomedicine carrying recombinant human Tumor Necrosis Factor α (TNFα)(CYT6091), resulting in vascular leakage, decreased IFP, and increased intratumoral concentration of paclitaxel in vivo. The purpose of this study is to investigate the mechanisms involved in a TNFα-induced reduction of IFP. We investigated the effects of TNF-α on cytokines and extracellular matrix (ECM) proteins in tumor microenvironment. Our data showed that TNFα treatment downregulated transforming growth factor-beta (TGF-β) and Lysyl oxidase (LOX) and upregulated several ECM proteins. However, we observed LOX upregulation when we treated thyroid cancer with siTNF-α-receptor 1 or 2 followed by TNF-α, suggesting the involvement of TNF-α-receptors in treatment resistance. In addition to the role of LOX in stiffening the ECM, causing a barrier to drug delivery, we showed overexpression of LOX in aggressive thyroid cancer. We observed increased vascular leakage in siLOX-treated thyroid cancer xenografts, mimicking the effect of CYT-6091. Furthermore, we confirmed that the LOX expression in thyroid cancer is positively associated with transforming growth factor receptor 1 (TGFBR1). In TCGA thyroid cancer database the mRNA expression of TGFBR1 was positively correlated with those of ECM regulatory genes (ITGB2, ITGA2 and COL1A1) which were downregulated with TNF-α treated thyroid cancer cells. To assess the role of TGF-β on vascular permeability, we found that the TGF-β inhibitor (SB-431542) induced in vitro vascular leakage, while the recombinant TGF-β reversed TNF-α-induced in vitro vascular leakage in HUVEC cells. SB-431542 and TGF-β neutralizing antibodies independently and markedly improved treatment efficacy of paclitaxel in in vitro thyroid cancer 3D tumor spheroids. Moreover, TGF-β1 inhibition downregulates the protein levels of Smad3 molecules in thyroid cancer cells. TCGA database studies of thyroid cancer patient samples showed that SMAD3 positively correlated with TGFBR1 and LOX, suggesting the involvement of SMAD3 in TGF-β/LOX signaling in the TME. Citation Format: DIPRANJAN LAHA. Targeting poorly differentiated and anaplastic thyroid cancer microenvironment via TNF-α/TGF-β/LOX signaling to improve drug delivery and treatment efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5796.
Abstract 1022: Disparities in accessibility to oncology care centers in France
Authors: Eric Daoud, Anne-Sophie Hamy, Elise Dumas, Lidia Delrieu, Beatriz Grandal, Christine Le Bihan-Benjamin, Sophie Houzard, Philippe-Jean Bousquet, Judicael Hotton, Aude-Marie Savoye, Christelle Jouannaud, Chloé-Agathe Azencott, Marc Lelarge, Reyal Fabien
Journal: Cancer Research (2022)

Abstract Background: Cancer caused nearly 10 million deaths in 2020. While most of the ongoing research focuses on finding new treatments, accessibility to oncology care receives less attention. However, access to health services plays a key role in cancer survival. Spatial accessibility methods have been successfully applied to measure accessibility to primary care. Yet, little research to date focused on oncology care specifically. Methods: We focused on all care centers with medicine, surgery, or obstetric activity in metropolitan France. We propose a clustering algorithm to automatically label the hospitals in terms of oncology specialization. Then, we computed an accessibility score to these hospitals for every municipality in metropolitan France. Finally, we proposed an optimization algorithm to increase the oncology accessibility by identifying centers which should increase their capacity. Results: We labelled 1,662 care centers into 8 clusters. Half of them were eligible for oncology care and 118 centers were identified as experts. We computed the oncology accessibility score for 34,877 municipalities in metropolitan France. Half of the population lived in the top 20% accessibility areas, and 6.3% in the bottom 20% zones. Accessibility was higher near dense cities, where the experts care centers were located. By combining the care centers clusters and the accessibility distributions, our optimization algorithm could identify hospitals to grow, to reduce accessibility disparities. Conclusion: Our method made it possible to quantify oncology care accessibility across all metropolitan France, as well as to make suggestions on where to increase hospital capacity to improve accessibility, especially in more populated suburban areas. Our approach was deliberately non-specific to cancer type nor to the kind of stays, but it could be adapted to more specific scenarios. We packaged our method into a web application allowing the users to run the algorithms with various parameters and visualize the results. Citation Format: Eric Daoud, Anne-Sophie Hamy, Elise Dumas, Lidia Delrieu, Beatriz Grandal, Christine Le Bihan-Benjamin, Sophie Houzard, Philippe-Jean Bousquet, Judicael Hotton, Aude-Marie Savoye, Christelle Jouannaud, Chloé-Agathe Azencott, Marc Lelarge, Reyal Fabien. Disparities in accessibility to oncology care centers in France [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1022.